Interleukin‐2 reconstitutes defective human immunodeficiency virus (HIV), and cytomegalovirus (CMV) specific CD8+ T cell proliferation in HIV infection

Abstract

Recent studies indicate that a defective proliferative response of HIV-specific CD8+ T cells is associated with the lack of virologic control in chronic HIV infection in humans. The possible mechanisms that might be responsible for the reduced proliferative potential of HIV-specific CD8+ T cells and conditions conducive to the proliferation of CD8+ T cells were examined in 14 HIV-infected individuals and 7 HIV-uninfected controls using CFSE labeling and flow cytometry techniques, and analyzed data using 2 quantitative measurements: the percentages of proliferating CD8+ T cells (Tp), and the maximum number of cell divisions (Dm) after stimulation. It was found that CD8+ T cells from HIV-infected and -uninfected subjects proliferated equally well after polyclonal stimulation by phylohemagglutinin A (PHA); both groups reached a Tp of 92%-96% and a Dm of 5-8. However, in HIV-infected subjects, proliferation of HIV- and CMV-specific CD8+ T cells was significantly reduced compared to proliferation of CMV- specific CD8+ T cells from HIV-uninfected subjects. These defective proliferative responses of HIV- and CMV-specific CD8+ T cells were restored by the addition of IL-2 at the time of stimulation. These results may have implications for the design of immune modulation strategies in vivo.

HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo

“…However, after in vitro generation, most HIV-specific CD8 ϩ T-cell lines contained a significant frequency of HIV-specific CD8 ϩ T cells that expressed CD28 and that yielded progeny in some individuals that retained qualities of CD8 ϩ Tcm after transfer in vivo as reflected by the ability of some infused clones to persist, secrete high levels of IL-2 and proliferate extensively on Ag re-encounter. These functional responses are distinct from those generally found in HIV-specific CD8 ϩ T cells in chronically infected HIV patients, 25,44,45 which likely reflects the fact that most of the responding cells have Tem characteristics. Accumulation over time of persisting cells that express CD28 and CD62L is consistent with the fate of LCMV-specific murine CD8 ϩ T cells found late after clearance of Ag 22 and in some respects similar to the accumulation of CD27 ϩ T cells in persisting cells after adoptive transfer studies in humans, 46,47 as CD27 can deliver an alternative costimulatory signal to CD28 that facilitates cell survival and function.…”

CD8 T-Cell Proliferative Capacity Is Compromised in Primary HIV-1 Infection

“…While studies have implicated IL-2 secretion from CD8 T cells as a signature phenotype of proliferators, our findings suggest it may only be a marker for a broader population of cells with heterogeneous functions. Disparate results have been published regarding the ability to recover defective CD8 T cell proliferation with the addition of exogenous IL-2 or CD4 T cells 18, 32, 33 . We were unable to recover CD8 proliferative capacity with the addition of IL-2 ex vivo, suggesting that CD4 mediated paracrine signaling does not support long term CD8 T cell proliferation.…”

Telomerase activity of HIV-1–specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors

“…23,24 In indicated experiments, PBMCs were initially exposed to a PD-L1-blocking antibody 25 for 16 hours in the presence of antigenic peptides (0.2 g/mL) and washed once before continuing incubation. On day 6, cells were harvested, washed with phosphate-buffered saline (PBS), and stained with monoclonal CD8 antibodies (Becton Dickinson) and, if indicated, MHC class I tetramers/pentamers refolded with the studied epitopic HIV-1 peptides.…”